Rifamycin compositions for the treatment of sarcopenia

Abstract

The present disclosure relates to compositions comprising rifamycin SV and their use in the treatment of sarcopenia. More specifically, the present disclosure describes pharmaceutical compositions comprising rifamycin SV for use in the treatment of sarcopenia in a subject suffering from a chronic disease.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 583,745, filed September 19, 2023, and U.S. Provisional Patent Application No. 63 / 589,236, filed October 10, 2023, each of which is incorporated herein by reference in its entirety.

[0003] Statement on Federally Funded Research

[0004] This invention was carried out with government support under a Collaborative Research and Development Agreement (CRADA) between the U.S. Department of Veterans Affairs and Cosmo Technologies Ltd., entitled "A Double-blind Randomized Controlled Trial of Rifamycin in Minimal Hepatic Encephalopathy," signed on May 6, 2019 (GCLAWS# 30233, Agreement No. 2019-0254). This invention is a CRADA project invention, and the government holds certain rights to it. Background Technology

[0005] Cirrhosis and associated cognitive impairments due to minimal hepatic encephalopathy (MHE) pose significant challenges to daily functioning and adverse clinical outcomes, such as the development of overt HE (OHE). The pathogenesis of MHE and OHE is linked to alterations in the gut-liver-brain axis, and drugs focusing on the gut microbiome have been successfully used for MHE. However, there is currently no standard treatment for MHE, and treatment is typically based on a case-by-case basis. In cirrhosis, the composition and function of the gut microbiome (changes in bile acids, endotoxemia, and gut metabolites) are altered, worsening as MHE and OHE progress. Current treatments for OHE primarily focus on the gut, including lactulose and rifaximin. However, despite their significant impact on disease progression, there are currently no guidelines for treating MHE. Previous studies using lactulose and rifaximin have been conducted in this context, improving brain function, changes in brain MRI, and microbiome function. However, a standard treatment still does not exist.

[0006] Rifamycin SV MMX® 200 mg is an intestinal-specific antibiotic with a long-standing safety record and has been approved by the FDA for the treatment of traveler's diarrhea. Unlike rifaximin, rifamycin-SV MMX primarily affects the colon, where the bacterial load is much higher than in other parts of the gastrointestinal tract. The effects of rifamycin on MHE have not been studied to date. Summary of the Invention

[0007] This disclosure relates to compositions comprising rifamycin SV (also referred to herein as rifamycin) and their use in the treatment of sarcopenia. More specifically, this disclosure describes pharmaceutical compositions comprising rifamycin SV for the treatment of sarcopenia in subjects with chronic diseases.

[0008] This article uses publications and other materials to clarify the background or provide additional details about the practice, which are incorporated by reference and, for convenience, are grouped separately in the bibliography.

[0009] This disclosure relates to compositions comprising rifamycin SV (also referred to herein as rifamycin) or a pharmaceutically acceptable salt thereof, and their use in the treatment of sarcopenia. A method for treating sarcopenia by administering an effective amount of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need is also disclosed.

[0010] This disclosure further relates to a method of treating sarcopenia by administering to a subject in need a composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, wherein the subject suffers from a chronic disease. This disclosure further relates to the use of pharmaceutical compositions comprising rifamycin SV as disclosed herein in the manufacture of medicaments for treating sarcopenia. This disclosure further relates to the use of pharmaceutical compositions comprising rifamycin SV as disclosed herein in the manufacture of medicaments for treating sarcopenia in subjects suffering from chronic diseases. This disclosure describes the use of rifamycin SV or a pharmaceutically acceptable salt thereof for treating, improving, reducing the severity of sarcopenia, inducing, maintaining remission of sarcopenia, and / or slowing the progression of sarcopenia. For example, methods for improving one or more symptoms of sarcopenia are disclosed herein. Furthermore, this disclosure describes the use of rifamycin SV or a pharmaceutically acceptable salt thereof for treating, improving, reducing the severity of sarcopenia, inducing, maintaining remission of sarcopenia, and / or slowing the progression of sarcopenia in subjects with chronic diseases. More specifically, this disclosure describes compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof for the treatment of, improvement of, reduction of severity of, induction of, maintenance of remission of, and / or slowing of the progression of sarcopenia. Furthermore, this disclosure describes compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof for the treatment of, improvement of, reduction of severity of, induction of, maintenance of remission of, and / or slowing of the progression of sarcopenia in subjects with chronic disease.

[0011] In one aspect, the present invention relates to a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients, said pharmaceutical composition being used in a method of treating sarcopenia.

[0012] The disclosed method of treating sarcopenia may involve administering to a patient in need about 200 mg, or about 400 mg, or about 600 mg, or about 800 mg, or about 1,000 mg, or about 1,200 mg, or about 1,400 mg, or about 1,600 mg, or about 1,800 mg, or about 2,000 mg, or about 2,200 mg, or about 2,400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. For example, the method may involve administering to a patient in need a pharmaceutical composition comprising about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the disclosed method may involve administering to a patient in need a pharmaceutical composition comprising about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the disclosed method of treating sarcopenia may involve administering one or more units of a pharmaceutical composition comprising about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to achieve a therapeutically effective amount. In some respects, the disclosed methods for treating sarcopenia may involve administering one or more units of a pharmaceutical composition comprising about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to achieve a therapeutically effective amount.

[0013] In some aspects, the method may include administering a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, which may comprise about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients. In some aspects, the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof may comprise about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0014] In some respects, the pharmaceutical composition is an oral dosage form, meaning the pharmaceutical composition is suitable for oral administration. The oral dosage form can be a capsule, a tablet, or a small tablet. Preferably, the oral dosage form is a tablet.

[0015] In some aspects, the pharmaceutical composition further comprises one or more of a lipophilic, hydrophilic, and amphiphilic substance. Preferably, the pharmaceutical composition comprises at least one lipophilic substance, at least one hydrophilic substance, and at least one amphiphilic substance. Preferably, the pharmaceutical composition comprises a controlled-release system characterized by the presence of a first amphiphilic matrix in which the active ingredient is incorporated, and the active ingredient is then dispersed in a second lipophilic matrix. The resulting form is then further dispersed in a third hydrophilic matrix, thus producing the final oral pharmaceutical form.

[0016] In some aspects, the lipophilic matrix of the compositions disclosed herein is represented by a substance having a melting point below 90°C, such as, for example, unsaturated alcohols or hydrogenated alcohols (such as cetyl alcohol, stearyl alcohol, myristic alcohol, lauryl alcohol, or oleyl alcohol) or their fatty acids, salts, esters (such as palmitic acid, stearic acid, myristic acid, lauric acid, or oleic acid); fatty acid monoglycerides, diglycerides, or triglycerides or their polyethoxylated derivatives, such as stearin; waxes, such as beeswax or carnauba wax; ceramides; cholesterol derivatives or mixtures thereof. One of the salts of stearic acid or thereof (such as, for example, magnesium stearate) is preferably at least one lipophilic compound. The lipophilic compound may be an ester of a hydrogenated fatty alcohol. The lipophilic compound may be sodium stearoyl fumarate.

[0017] Hydrophilic matrices may contain substances such as cellulose derivatives, such as hydroxyalkyl cellulose, alkyl cellulose, carboxyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, and anionic or cationic polysaccharide derivatives, such as, for example, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or their derivatives. Hydrophilic matrices can also be represented by typically cross-linked or linear polymer or copolymer substances, referred to as hydrogels, that is, substances that undergo so-called “molecular relaxation” upon transitioning from a dry state to a hydrated state; this molecular relaxation is a significant increase in mass and weight resulting from the coordination of a large number of water molecules through polar groups present in their polymer chains. Specifically, at least one hydrophilic substance may be selected from cellulose derivatives and their esters and / or salts, such as hydroxyalkyl cellulose (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium hydroxypropyl methyl cellulose), alkyl cellulose, carboxylalkyl cellulose (e.g., sodium carboxymethyl cellulose); polyvinyl alcohol; carboxyvinyl derivatives; polysaccharides, such as dextrin, pectin, starch and their derivatives; natural or synthetic gums; alginic acid; polyols, such as xylitol, maltitol or mannitol.

[0018] In some aspects, the pharmaceutical composition may further comprise at least one other excipient, such as an antioxidant, chelating agent, preservative, antimicrobial agent, surfactant, co-surfactant, lipophilic compound, purified water, organic salt, inorganic salt, buffer, or mixture thereof. Suitably, the pharmaceutical composition may further comprise at least one antioxidant and at least one preservative.

[0019] In some aspects, the amphiphilic matrix may be represented by substances selected from the group consisting of, for example, phospholipids, ceramides, sphingomyelin, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl groups, and sorbitol derivatives, while the hydrophilic matrix may be represented by typically cross-linked or linear polymers or copolymers, referred to as hydrogels, meaning substances that, upon contact with water molecules, increase their mass and weight due to the polar groups present in the polymer backbone or side chains. In some aspects, the amphiphilic matrix may contain substances selected from the group consisting of: type I or type II polar lipids (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, ethylene glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol®), natural or synthetic gums, polyoxyethylene sorbitol monooleate, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. Lecithin is preferably at least one amphiphilic compound in the composition.

[0020] In some respects, the matrix and active ingredient are continuously dispersed together in each other, thereby forming a site-specific, homogeneous structure responsible for release.

[0021] In some respects, the pharmaceutical compositions disclosed herein may also contain at least one physiologically acceptable excipient, such as a bioadhesive excipient, such as chitosan, polyacrylamide, natural or synthetic gums, acrylic polymers and copolymers.

[0022] In some aspects, the pharmaceutical compositions disclosed herein may further comprise a gastric-tolerant coating. In some aspects, the oral pharmaceutical compositions of the present invention may be coated with a gastric-tolerant coating (film) that may contain polymethacrylate, acrylic acid and / or methacrylate polymers or copolymers, or cellulose derivatives, such as cellulose acetylated phthalate. Preferably, the gastric protective coating contains polymethacrylate, including but not limited to compounds commercially known as Eudragit S100 (methyl methacrylate copolymer) 1:2, Eudragit L100 (methyl methacrylate copolymer) and / or Eudragit L30 D55 (ethyl methacrylate copolymer). In some aspects, the gastric protective coating may contain methyl methacrylate copolymer (Eudragit L100). In some aspects, the gastric protective coating may contain ethyl methacrylate copolymer (Eudragit L30 D55). Suitably, the gastric tolerance coating (film) may contain a 1:2 copolymer of methyl methacrylate and methacrylate (Eudragit S100). In some aspects, the gastric protective coating contains a mixture of a 1:1 copolymer of methyl methacrylate and methacrylate (Eudragit L100) and a 1:2 copolymer of methyl methacrylate and methacrylate (Eudragit S100). In some aspects, the gastric tolerance coating (film) may further comprise one or more of the following: talc, triethyl citrate, titanium dioxide, and one or more compounds that impart color to the oral pharmaceutical composition.

[0023] This document discloses the use of pharmaceutical compositions comprising rifamycin SV or pharmaceutically acceptable salts thereof for the treatment of, improvement of, reduction of severity of, slowing of progression of, induction of remission of, or maintenance of remission of sarcopenia.

[0024] Methods for treating, improving, reducing, slowing, inducing, or maintaining sarcopenia are disclosed, the methods comprising administering to a patient in need a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein. Methods for treating, improving, reducing, slowing, inducing, or maintaining sarcopenia are disclosed, the methods comprising administering to a patient in need a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein, the patient having a chronic disease.

[0025] Methods for treating, improving, reducing, slowing, inducing, or maintaining remission of sarcopenia are disclosed, the methods comprising administering to a patient in need a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein, the patient having a chronic disease. Suitably, the chronic disease is selected from cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, or end-stage lung disease. Preferably, the chronic disease is cirrhosis and / or hepatic encephalopathy.

[0026] In some respects, the pharmaceutical compositions disclosed herein can be administered orally to human patients.

[0027] In some aspects, the use of pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament for treating sarcopenia is disclosed. In other aspects, the use of pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament for treating sarcopenia associated with a chronic disease is disclosed.

[0028] In some aspects, the use of pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament for treating sarcopenia in patients with chronic diseases is disclosed. In some aspects, the chronic disease is selected from cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, or end-stage lung disease. In some aspects, the chronic disease is cirrhosis and / or hepatic encephalopathy.

[0029] Further advantages of the disclosed methods and compositions will be set forth in part in the description which follows, and will be understood in part from the description, or may be learned by practice of the disclosed methods and compositions. The advantages of the disclosed methods and compositions will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and do not limit the claimed invention. Attached Figure Description

[0030] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate some embodiments of the disclosed methods and compositions and, together with the specification, serve to explain the principles of the disclosed methods and compositions.

[0031] Figures 1A-1B Examples of research design flowcharts and flowchart templates conforming to the CONSORT guidelines are shown respectively.

[0032] Figures 2A-2D The study showed comparisons of fecal microbiota between rifamycin baseline and study endpoint, and between rifamycin and placebo endpoint. Figure 2AComparison of linear discriminant function effect sizes between the rifamycin endpoint and baseline, and between the rifamycin and placebo endpoints. Figure 2B (Separate plots of CDR and increment within the rifamycin group at baseline and endpoint (day 30)). Figure 2C (Rifampicin baseline (right oval) vs. endpoint (left oval) PERMANOVA F value 2.529, p=0.014). Figure 2D The placebo endpoint (large ellipse on the left) and the rifamycin endpoint (smaller ellipse inside the placebo) were compared using the PERMANOVA F-value of 3.349 (p = 0.003).

[0033] Figure 3 The study showed a comparison of fecal microbiota, revealing that rifamycin resulted in lower alpha diversity and a lower rate of dysbiosis in liver cirrhosis compared to placebo.

[0034] Figures 4A-4D Showing changes in lean body mass ( Figure 4A Changes in grip strength Figure 4B Changes in ammonia () Figure 4C ) and changes in fecal butyrate ( Figure 4D ).

[0035] Figures 5A-5D This shows a summary of the findings based on Example 1. Figure 5A It shows the changes between and within groups at baseline and study endpoint; Figure 5B This shows the difference in change from baseline to the study endpoint between the two groups; Figure 5C The comparison between the placebo endpoint and the RiVM endpoint is shown, with purple dots in the ellipse indicating individual clusters; Figure 5D The comparison between the RiVM baseline and the RiVM endpoint is shown, with the blue dots in the ellipse representing individual clusters. Detailed Implementation

[0036] The disclosed methods and compositions can be more readily understood by referring to the following detailed description of specific embodiments and examples included therein, as well as the accompanying drawings and their preceding and following descriptions.

[0037] It should be understood that, unless otherwise stated, the disclosed methods and compositions are not limited to specific synthetic methods, specific analytical techniques, or specific reagents, and therefore can be varied. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0038] Materials, compositions, and components that can be used in, in conjunction with, or to prepare the disclosed methods and compositions, or products of the disclosed methods and compositions, are disclosed herein. These and other materials are disclosed herein, and it should be understood that while specific references to every different individual and collective combination and arrangement of these compounds are not explicitly disclosed when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each is specifically considered and described herein. For example, if a peptide is disclosed and discussed, and numerous modifications that can be made to multiple molecules containing said amino acids are discussed, then each combination and arrangement of said peptides, as well as possible modifications, are specifically considered unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and an example of the combination molecule AD is disclosed, then each is considered individually and uniformly, even if each is not individually listed. Therefore, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically considered and should be regarded as disclosed by the disclosures of A, B, and C; D, E, and F; and the example combination AD. Similarly, any subsets or combinations of these are also specifically contemplated and disclosed. Thus, for example, subgroups of AE, BF, and CE are specifically contemplated and should be considered as disclosed by the disclosures of A, B, and C; D, E, and F; and the example combination AD. This concept applies to all aspects of this application, including but not limited to steps in methods of preparing and using the disclosed compositions. Therefore, if there are multiple additional steps that can be performed, it should be understood that each of these additional steps can be performed using any particular embodiment or combination of embodiments of the disclosed methods, and each such combination is specifically contemplated and should be considered as disclosed.

[0039] A. Definition

[0040] It should be understood that the disclosed methods and compositions are not limited to the specific methods, schemes, and reagents described, as these can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the appended claims.

[0041] It should be understood that the disclosed methods and compositions are not limited to the specific methods, schemes, and reagents described, as these can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined only by the appended claims.

[0042] It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used herein and in the appended claims include plural references. Thus, for example, reference to “subject” includes a plurality of such subjects, reference to “subject” refers to one or more subjects and their equivalents known to those skilled in the art, and so on.

[0043] As used herein, the word “or” means any one member of a particular list, and also includes any combination of members of said list. The term “and / or” means any one of the items associated with said term, any combination of those items, or all of those items.

[0044] As used herein, the term "therapeutic effective amount" means an amount of a therapeutic, preventive, and / or diagnostic agent sufficient to treat, alleviate, improve, reduce, alleviate symptoms of, prevent, delay onset, inhibit progression, reduce severity, and / or reduce morbidity of a disease, condition, and / or symptom when administered to a subject who has or is susceptible to the disease, condition, and / or symptom. In this context, the therapeutic effective amount of rifamycin SV is the amount of rifamycin SV required to treat, improve, reduce severity, slow progression, induce remission, or maintain remission of sarcopenia when administered to a patient in need. Optionally, the patient in need may have a chronic disease.

[0045] As used herein, the term "treatment" means the partial or complete relief, improvement, reduction, or elimination of one or more symptoms or features of a particular disease, symptom, and / or condition; delaying its onset; inhibiting its progression; reducing its severity; and / or decreasing its incidence. Treatment may be administered to subjects who do not exhibit signs of a disease, symptom, and / or condition and / or who exhibit only early signs of a disease, symptom, and / or condition for the purpose of reducing the risk of developing a pathology associated with the disease, symptom, and / or condition.

[0046] As used herein, “sample” means an animal; tissue or organ derived from an animal; cells (in the subject, taken directly from the subject, or maintained in a culture or derived from a cultured cell line); cell lysates (or lysate fractions) or cell extracts; or a solution containing one or more molecules (e.g., polypeptides or nucleic acids) derived from cells or cellular material, which are measured as described herein. A sample can also be any bodily fluid or excretion containing cells or cellular components (e.g., but not limited to blood, urine, feces, saliva, tears, bile).

[0047] As used herein, “subject” refers to the target of administration, for example, an animal. Therefore, the subject of the disclosed methods can be a vertebrate, such as a mammal. For example, a subject can be a human. The term does not indicate a specific age or sex. Subject may be used interchangeably with “individual” or “patient”.

[0048] Ranges herein may be expressed as from “about” one particular value and / or to “about” another particular value. When expressing such ranges, unless the context explicitly states otherwise, it is also specifically anticipated that a range from one particular value and / or to another particular value is disclosed. Similarly, when values ​​are expressed as approximate values ​​using the antecedent “about,” it should be understood that, unless the context explicitly indicates otherwise, said particular value forms another embodiment that should be considered disclosed by particular careful consideration. It should be further understood that, unless the context explicitly indicates otherwise, the endpoints of each range are significant relative to and independent of the other endpoint. Finally, it should be understood that, unless the context explicitly indicates otherwise, all individual values ​​and subranges of values ​​contained within the explicitly disclosed range are also specifically considered by careful consideration and should be considered disclosed. The foregoing applies regardless of whether some or all of these embodiments are explicitly disclosed in a particular case.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed methods and compositions pertain. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of these methods and compositions, particularly useful methods, apparatuses, and materials are as described. The publications cited herein and the materials they reference are hereby incorporated by reference. Nothing herein should be construed as an admission that the invention is not authorized prior to such disclosure by means of prior art. No reference is acknowledged to constitute prior art. The discussion of the references states what their authors claim, and the applicant reserves the right to question the accuracy and relevance of the cited references. It should be clearly understood that although this document references numerous publications, such references do not constitute an admission that any of these publications constitutes part of common general knowledge in the art.

[0050] Throughout the detailed description and claims, the word "comprise" and variations thereof, such as "comprising" and "comprises," mean "including but not limited to" and are not intended to exclude, for example, other additives, components, integers, or steps. In particular, in methods stated as comprising one or more steps or operations, each step is specifically considered to include the listed contents (unless the step includes restrictive terms such as "consisting of"), meaning that each step is not intended to exclude, for example, other additives, components, integers, or steps not listed in the step. The terms "consist essentially of" and "consisting essentially of" should be interpreted as semi-closed terms, meaning excluding other components that substantially affect the essential and novel features of the invention (and optionally including physiologically acceptable excipients and / or adjuvants).

[0051] References to “an embodiment,” “an embodiment,” “an aspect,” “aspect,” and similar terms in the specification indicate that the described embodiment or aspect may include a particular aspect, feature, structure, or characteristic. Furthermore, such phrases may, but do not necessarily, refer to the same embodiment or aspect mentioned in other parts of the specification. Additionally, when a particular aspect, feature, structure, or characteristic is described in connection with an embodiment or aspect, whether explicitly stated or not, the influence of said aspect, feature, structure, or characteristic on or relating to other embodiments or aspects is within the knowledge of a person skilled in the art. Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Thus, for example, a reference to “a compound” includes multiple such compounds. It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a precondition for the use of exclusive terms such as “solely,” “only,” or the use of “negative” restrictions in the recitation of elements of the claims.

[0052] The term "placebo" is intended to refer to a pharmaceutical composition that does not contain an active ingredient. Therefore, in its simplest usage, a "placebo" contains excipients or carriers suitable for formulating a pharmaceutical composition, without incorporating any active substance.

[0053] Those skilled in the art will understand that, for any and all purposes, particularly in providing a written description, all ranges described herein also encompass any and all possible subranges and combinations thereof, as well as the individual values ​​constituting the ranges, particularly integer values. The described ranges include every specific value, integer, decimal, or identity within the ranges.

[0054] Those skilled in the art will recognize that, where members are grouped together in a common manner, such as in a Markush group, the invention covers not only the entire group listed as a whole, but also each member of said group and all possible subgroups of the main group individually. Furthermore, for all purposes, the invention covers not only the main group, but also the main group lacking one or more members. Therefore, the invention contemplates the explicit exclusion of any one or more members of the described groups. Consequently, accompanying conditions may be applied to any disclosed category or embodiment, thereby excluding any one or more of the described elements, kinds, or embodiments from such category or embodiment, for example, as used for explicit negative limitation.

[0055] The term "relief" refers to the reduction of symptoms and / or manifestations of inflammation and / or degenerative diseases of the gastrointestinal tract.

[0056] The term "reduction" refers to reducing the degree of damage caused by inflammation and / or degenerative diseases of the gastrointestinal tract or reducing the clinical signs or symptoms associated with such damage.

[0057] "Rifampicin SV" refers to rifamycin, defined as CAS No. 6998-60-3. Rifamycin SV sodium or rifamycin sodium salt refers to the sodium salt of rifamycin SV, defined as CAS No. 14897-39-3.

[0058] The term "long-lasting" refers to the time that a formulation must remain at the site of action to exert its therapeutic effect.

[0059] The expression "600 mg rifamycin SV or a pharmaceutically acceptable salt thereof" in this document refers to 600 mg of rifamycin SV as dry matter (anhydrous) or 600 mg of a pharmaceutically acceptable salt of rifamycin SV as dry matter, including but not limited to 600 mg of a sodium salt of rifamycin SV, or an equivalent amount of a pharmaceutically acceptable salt of rifamycin SV as dry matter (anhydrous). In one aspect, 600 mg of a sodium salt of rifamycin SV as dry matter is equivalent to 582 mg of rifamycin SV as dry matter. In another aspect, 600 mg of a sodium salt of rifamycin SV is equivalent to 582 mg of rifamycin SV as dry matter and 18 mg of sodium ions. In yet another aspect, 600 mg of rifamycin SV as dry matter is equivalent to 618 mg of a sodium salt of rifamycin SV. In yet another aspect, 618 mg of a sodium salt of rifamycin SV is equivalent to 600 mg of rifamycin SV and 18 mg of sodium ions.

[0060] As used herein, the terms “approximately” and “about” refer to the range of experimental errors that may occur in a measurement, such as, for example, 10%, 5%, 2.5%, 2%, or 1% error. For example, about 200 mg could be 200 mg ± 10%, or 200 mg ± 5%, or 200 mg ± 2.5%, or 200 mg ± 2%, or 200 ± 1%. For example, about 200 mg is a range of 180 mg to 220 mg, or 190 mg to 210 mg, or 195 mg to 205 mg, or 196 mg to 204 mg, or 199 mg to 201 mg. Similarly, about 400 mg could be 400 mg ± 10%, or 400 mg ± 5%, or 400 mg ± 2.5%, or 400 mg ± 2%, or 400 ± 1%. For example, about 400 mg is a range of 360 mg to 440 mg, or 380 mg to 420 mg, or 390 mg to 410 mg, or 392 mg to 408 mg, or 396 mg to 404 mg. Similarly, about 600 mg can be 600 mg ± 10%, or 600 mg ± 5%, or 600 mg ± 2.5%, or 600 mg ± 2%, or 600 mg ± 1%. For example, about 600 mg is a range of 540 mg to 660 mg, or 570 mg to 630 mg, or 585 mg to 615 mg, or 588 mg to 612 mg, or 594 mg to 606 mg.

[0061] As used in this article, the term "MELD" stands for Model for End-Stage Liver Disease, also known as Mayo End-Stage Liver Disease, a scoring system used to stage end-stage liver disease. Descriptions of the scoring system are provided in professional scientific literature, such as Hepatology, Vol. 45, No. 3, March 2007, pp. 797-805.

[0062] As used in this article, the term "Child score" refers to the Child-Pugh score (or Child-Turcotte-Pugh (CTP) score or Child criteria), which is a scoring system used to assess the prognosis of chronic liver diseases, primarily cirrhosis. Descriptions of the score are provided in professional scientific literature, such as Alimentary Pharmacology & Therapeutics.22 (11–12): 1079–89.

[0063] As used in this article, the acronym "AST" refers to aspartate aminotransferase or aspartate aminotransferase.

[0064] As used in this article, the acronym "ALT" refers to alanine aminotransferase.

[0065] As used in this article, the acronym "CHF" refers to congestive heart failure. The acronym "EF" refers to ejection fraction.

[0066] As used in this article, the acronym "COPD" refers to chronic obstructive pulmonary disease.

[0067] As used in this article, the acronym "PHES" refers to the psychometric hepatic encephalopathy score. Descriptions of the score are provided in professional scientific literature, such as the Journal of Clinical Medicine 2023 Jan; 12(2): 519.

[0068] The acronym "PO" stands for "Per os" and means oral administration.

[0069] The acronym "HRQOL" stands for Health-Related Quality of Life.

[0070] The acronym "AE" stands for "adverse event," and the acronym "SAE" stands for "serious adverse event."

[0071] The acronym "MRI" stands for Magnetic Resonance Imaging.

[0072] The acronym "SCFA" stands for short-chain fatty acids. Exemplary short-chain fatty acids include, but are not limited to: acetic acid and its salts (acetates); propionic acid and its salts (propionates); butyric acid and its salts (butyrates); isobutyric acid and its salts (isobutyrates); valeric acid and its salts (valerates); isovaleric acid and its salts (isovalerates); 2-methylbutyric acid and its salts (2-methylbutyrates); hexanoic acid and its salts (hexanoates); and so on.

[0073] B. Pharmaceutical Composition

[0074] Pharmaceutical compositions that can be used in the methods disclosed herein are disclosed. Pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients are disclosed. In some aspects, one or more carriers and / or excipients may be referred to as pharmaceutically acceptable carriers. Examples of pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof also include the compositions shown in Tables 1-3 disclosed herein.

[0075] In some respects, the pharmaceutical composition has a multi-matrix structure comprising an amphiphilic matrix incorporating rifamycin SV; a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the amphiphilic matrix is ​​dispersed; and a hydrophilic matrix.

[0076] A pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients is disclosed, said pharmaceutical composition being used to treat sarcopenia.

[0077] In some aspects, the pharmaceutical composition may be one or more of the pharmaceutical compositions disclosed herein. In some aspects, the pharmaceutical composition has a multi-matrix structure comprising an amphiphilic matrix incorporating rifamycin SV; a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the amphiphilic matrix is ​​dispersed; and a hydrophilic matrix.

[0078] In some aspects, the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. In some aspects, the amphiphilic substance may be present in an amount ranging from 0.001% to 0.0500% by weight, or 0.005% to 0.050% by weight, or 0.005% to 0.030% by weight of the composition.

[0079] In some aspects, the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts. In some aspects, the lipophilic substance may be present in an amount ranging from 0.01% to 0.050% by weight, or 0.01% to 0.035% by weight, or 0.015% to 0.025% by weight of the composition.

[0080] In some aspects, the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol. In some aspects, the hydrophilic substance may be present in an amount ranging from 0.05% to 0.50% by weight, or 0.1% to 0.5% by weight, or 0.1% to 0.3% by weight of the composition.

[0081] In some aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing stearic acid, and a hydrophilic matrix containing sodium carboxymethyl cellulose. In other aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing glyceryl distearate, and a hydrophilic matrix of ammonium methacrylate copolymer (type B).

[0082] In some aspects, the pharmaceutical composition further comprises a gastric-tolerant (or enteric) coating. In some aspects, the pharmaceutical composition may comprise a gastric-tolerant coating dissolved at a pH of about 5, or about 5.5, or about 6.0, or about 6.2, or about 6.4, or about 6.6, or about 6.8, or about 7.0, or about 7.1, or about 7.2. In some aspects, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.4. In another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.8. In yet another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 7.0. In yet another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 7.2. In some aspects, the gastric-tolerant coating may comprise shellac, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose succinate acetate. In other aspects, the gastric-tolerant coating (film) covering the tablet core may contain polymethacrylate, acrylic and / or methacrylate polymers or copolymers, or cellulose derivatives such as cellulose acetylated phthalate. Optionally, the gastric protective coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L). Optionally, the gastric-tolerant coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (e.g., commercially known as EUDRAGIT S). Optionally, the gastric-tolerant coating comprises a methacrylate-ethyl acrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L30 D55). Optionally, the gastric protective coating comprises a polymethacrylate copolymer, including but not limited to compounds and / or mixtures thereof commercially known as EUDRAGIT S (methacrylic acid-methyl methacrylate copolymer 1:2), EUDRAGIT L (methacrylic acid-methyl methacrylate copolymer 1:1), and / or EUDRAGIT L30 D55 (methacrylic acid-ethyl acrylate copolymer 1:1). The gastric tolerance coating may comprise a methacrylic acid-(meth)acrylate copolymer. In some embodiments, the gastric tolerance coating comprises a methacrylic acid / methyl methacrylate copolymer.

[0083] Gastric tolerance coatings may contain methacrylic acid / methyl methacrylate (1:1) copolymer (EUDRAGIT L) or methacrylic acid / methyl methacrylate (1:2) copolymer (EUDRAGIT S).

[0084] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (EUDRAGITL).

[0085] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (EUDRAGITS).

[0086] In some embodiments, the gastric tolerance coating comprises a mixture of a 1:1 copolymer of methacrylic acid and a 1:2 copolymer of methacrylic acid and methyl methacrylate. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 0.5:1 to 3:1. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 1:1 to 3:1. In some embodiments, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of about 2:1.

[0087] Optionally, a unit dose of the gastric tolerance coating begins to rupture or dissolve at pH 5 or higher, or optionally at about pH 6 or higher, at pH 6.5 or higher, or at pH 6.8.

[0088] In some embodiments, the active substance is released from the tablet core at a pH of at least 5, such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, the active substance is released from the tablet core at a pH in the range of about 6.5 to about 7.5, optionally at a pH in the range of about 6.8 to about 7. According to one aspect, the active substance is released from the tablet core at pH 6.8. According to another aspect, the active substance is released from the tablet core at pH 7. According to a further aspect, the active substance is released from the tablet core at pH 7.2.

[0089] In some aspects, the pharmaceutical composition comprises a tablet core and a coating covering said core. In some aspects, the coating may be a gastric-tolerant coating, a delayed-release coating, or a prolonged-release coating.

[0090] In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (i.e., in the cecum).

[0091] In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine (duodenum, jejunum, and ileum)) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum) and optionally continues throughout the large intestine.

[0092] In some respects, the pharmaceutical composition is suitable for any known administration, particularly those described herein. In some respects, the pharmaceutical composition is suitable for oral administration. In other respects, the pharmaceutical composition is suitable for rectal administration. In a further respect, the pharmaceutical composition is suitable for parenteral administration, including intravenous, intramuscular, or subcutaneous injection. In a preferred respect, the pharmaceutical composition is suitable for oral administration.

[0093] This document discloses a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients for the treatment of sarcopenia, wherein the pharmaceutical composition has a multi-matrix structure comprising: a) an amphiphilic matrix incorporating rifamycin SV; b) a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the lipophilic matrix of a) is dispersed; and c) a hydrophilic matrix; wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers; wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated... The pharmaceutical composition comprises: ethanol or fatty acids, their salts or esters; monoglycerides, diglycerides or triglycerides of fatty acids or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts; wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxyalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol or mannitol; wherein the pharmaceutical composition further comprises a gastric-tolerant coating; wherein the pharmaceutical composition comprises a tablet core and a coating covering the core; and wherein the pharmaceutical composition is suitable for oral administration.

[0094] In some aspects, the pharmaceutical composition may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 1,100 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0095] In some aspects, the pharmaceutical composition may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0096] In some respects, the compositions disclosed herein may further comprise a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” means a material or carrier, as is well known to those skilled in the art, which will be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects on the subject.

[0097] Parenteral formulations comprise sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions containing saline and buffer media. Parenteral media include sodium chloride solutions, Ringer's dextran, dextran and sodium chloride, lactated Ringer's, or fixed oils. Intravenous media include fluids and nutritional supplements, electrolyte supplements (such as those based on Ringer's dextran), etc. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, and inert gases.

[0098] The disclosed rifamycin SV or a pharmaceutically acceptable salt thereof can be formulated in and / or administered in a pharmaceutically acceptable carrier, or formulated and / or administered with a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" can refer to sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders intended for recombination into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Suitable flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Preventing microbial activity can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. Isotonic agents, such as sugars and sodium chloride, may also be required. Absorption of injectable drug forms can be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable depot forms can be prepared by forming a microcapsule matrix of the drug in biodegradable polymers such as polylactic-polyglycolic acid, poly(orthoester), and poly(anhydride). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Depot-type injectable formulations are also prepared by retaining the drug in liposomes or microemulsions that are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacterial trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media just before use. Suitable inert carriers may include sugars, such as lactose. Ideally, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 micrometers.

[0099] In some aspects, the compositions disclosed herein may comprise lipids, such as liposomes, such as cationic liposomes (e.g., DOTMA, DOPE, DC-cholesterol) or anionic liposomes. If desired, the liposomes may further comprise proteins to facilitate targeting of specific cells. Administration of compositions comprising peptides and cationic liposomes may be administered to blood, target organs, or inhaled into the respiratory tract to target cells. For example, compositions comprising the peptide or nucleic acid sequence described herein, along with cationic liposomes, may be administered to lung cells of a subject. Regarding liposomes, see, for example, Brigham et al. Am. J. Resp. Cell. Mol. Biol. 1:95 100 (1989); Felgner et al. Proc. Natl. Acad. Sci USA 84:74137417 (1987); U.S. Patent No. 4,897,355. Furthermore, the compounds may be administered as components of microcapsules that may be targeted to specific cell types, such as macrophages, or in which the diffusion of the compound or delivery of the compound from the microcapsule is programmed to a specific rate or dose.

[0100] In some aspects, pharmaceutical compositions are disclosed comprising any of the rifamycin SVs disclosed herein or pharmaceutically acceptable salts or solvates thereof, and pharmaceutically acceptable carriers, buffers, or diluents. In some aspects, the delivery medium is a liposome, microcapsule, or nanoparticle. In yet another aspect, the delivery medium is PEGylated.

[0101] In the methods described herein, the composition can be delivered to cells via a variety of mechanisms. As defined above, this document discloses compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof as described herein, and may also include a carrier, such as a pharmaceutically acceptable carrier. For example, pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are disclosed. In some aspects, pharmaceutical compositions comprising the disclosed rifamycin SV or a pharmaceutically acceptable salt thereof are disclosed. That is, pharmaceutical compositions may be provided comprising a therapeutically effective amount of at least one disclosed rifamycin SV or a pharmaceutically acceptable salt thereof, or at least one product of the disclosed methods, and a pharmaceutically acceptable carrier.

[0102] In some aspects, the disclosed pharmaceutical compositions may comprise the disclosed rifamycin SV (including pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions of the present invention include those suitable for nasal, oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration; however, the most suitable route in any given case will depend on the specific host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be readily available in unit dosage forms and prepared by any method well known in the pharmaceutical field.

[0103] In practice, rifamycin SV or its pharmaceutically acceptable salts described herein can be tightly mixed with a drug carrier as the active ingredient using conventional pharmaceutical compounding techniques. The carrier can take various forms, depending on the desired formulation for administration (e.g., oral or parenteral (including intravenous)). Therefore, the pharmaceutical compositions of the present invention can exist as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can exist as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the common dosage forms listed above, the compounds of the present invention and / or their pharmaceutically acceptable salts can also be administered by controlled-release means and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally, such methods involve the step of bringing the active ingredient to association with a carrier constituting one or more essential components. Generally, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a finely fractionated solid carrier, or both. The product can then be conveniently shaped into the desired appearance.

[0104] The drug carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Other examples of carriers include dimyristoylphosphatidylcholine (DMPC), phosphate-buffered saline, or multivesicular liposomes. For example, PG:PC:cholesterol:peptide or PC:peptide can be used as a carrier in this invention. Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th edition), edited by AR Gennaro, Mack Publishing Company, Easton, PA 1995. Generally, an appropriate amount of pharmaceutically acceptable salt is used in the formulation to make the preparation isotonic. Other examples of pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's solution, and dextran solution. The pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5. Other carriers include sustained-release formulations, such as a semi-permeable matrix containing a solid hydrophobic polymer of the composition, said matrix being in the form of a molded article, such as a membrane, a stent (implanted into a blood vessel during angioplasty), liposomes, or microparticles. It will be apparent to those skilled in the art that certain carriers may be preferred, depending, for example, on the route of administration and the concentration of the composition administered. These will most typically be standard carriers used for administering drugs to humans, comprising solutions such as sterile water, saline, and buffer solutions at physiological pH.

[0105] To enhance the solubility and / or stability of the active ingredient in a pharmaceutical composition, the use of α-, β-, or γ-cyclodextrins or their derivatives may be advantageous, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Furthermore, co-solvents (such as alcohols) can improve the solubility and / or stability of the compounds according to the invention in the pharmaceutical composition.

[0106] The pharmaceutical composition may also contain carriers, thickeners, diluents, buffers, preservatives, etc., as long as they do not impair the intended activity of the active substance of the present invention. The pharmaceutical composition may also contain one or more active ingredients (other than those in the compositions of the present invention), such as antimicrobial agents, anti-inflammatory agents, anesthetics, etc. Depending on whether local or systemic treatment is required and the area to be treated, the pharmaceutical composition can be applied in many ways.

[0107] Because of their ease of administration, oral administration can be used, and tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid drug carriers are obviously employed. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid dosage forms, such as suspensions, elixirs, and solutions; while carriers (such as starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc.) can be used to form oral solid dosage forms, such as powders, capsules, and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units, thus solid drug carriers are employed. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0108] Compositions intended for oral administration may include powders or granules, suspensions or solutions in aqueous or non-aqueous media, capsules, sacs, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersants, or binders may be desired. Some compositions may potentially be administered as pharmaceutically acceptable acid or base addition salts formed by reaction with: inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanate, sulfuric acid, and phosphoric acid; and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid; or formed by reaction with: inorganic bases, such as sodium hydroxide, ammonium hydroxide, and potassium hydroxide; and organic bases, such as monoalkylamines, dialkylamines, trialkylamines, and arylamines, as well as substituted ethanolamines.

[0109] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally together with one or more excipients or adjuvants. Compressed tablets can be prepared by compression of the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0110] The pharmaceutical compositions of the present invention comprise, as an active ingredient, the disclosed rifamycin SV or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and optionally one or more other therapeutic agents or adjuvants. The compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the specific host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be readily available in unit dosage forms and prepared by any method well known in the pharmaceutical field.

[0111] Parenteral formulations comprise sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions containing saline and buffer media. Parenteral media include sodium chloride solutions, Ringer's dextran, dextran and sodium chloride, lactated Ringer's, or fixed oils. Intravenous media include fluids and nutritional supplements, electrolyte supplements (such as those based on Ringer's dextran), etc. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, and inert gases.

[0112] The pharmaceutical compositions of the present invention suitable for injectable use comprise sterile aqueous solutions or dispersions. Alternatively, the compositions may be in the form of sterile powders for provisional preparation of such sterile injectable solutions or dispersions. Generally, the final injectable form should be sterile and should be an effective fluid for easy injection. The pharmaceutical compositions should be stable under the conditions of production and storage; therefore, they should preferably be preserved to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0113] For example, injectable solutions can be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc., can be used. Solid formulations intended to be converted into a liquid form shortly before use are also included.

[0114] Parenteral formulations comprise sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions containing saline and buffer media. Parenteral media include sodium chloride solutions, Ringer's dextran, dextran and sodium chloride, lactated Ringer's, or fixed oils. Intravenous media include fluids and nutritional supplements, electrolyte supplements (such as those based on Ringer's dextran), etc. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, and inert gases.

[0115] In some aspects, the pharmaceutical compositions disclosed herein may be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture is formed into a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be conveniently formed by first mixing the composition with a softened or melted carrier, and then cooling and shaping it in a mold.

[0116] In addition to the aforementioned carrier components, the pharmaceutical formulations described herein may, as appropriate, include one or more other carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the intended receptor. Compositions containing rifamycin SV or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0117] The exact dosage and frequency of administration depend on the specific condition being treated and its severity; various factors specific to the subject's medical history, such as age; the subject's weight, sex, severity of illness, and general physical condition; and other medications the individual may be taking; and are well known to those skilled in the art. Furthermore, it is apparent that the effective daily dose may be reduced or increased depending on the response of the treated subject and / or on the assessment of the physician prescribing the composition.

[0118] Depending on the mode of administration, the pharmaceutical composition will comprise 0.05 to 99% by weight, preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight, of the active ingredient, and 1 to 99.95% by weight, preferably 30 to 99.9% by weight, more preferably 50 to 99.9% by weight, of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0119] C. Method

[0120] A method is disclosed comprising administering a therapeutically effective amount of a pharmaceutical composition to a subject, said pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more loaders and / or excipients as required thereto.

[0121] 1. Treatment of sarcopenia

[0122] A method for treating a subject with sarcopenia is disclosed, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients. A method for improving sarcopenia symptoms in a subject with sarcopenia is also disclosed, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients. Symptoms of sarcopenia may include, but are not limited to, loss of endurance, difficulty with daily activities, slow walking, poor balance, muscle atrophy, loss of balance, falls resulting in fractures and bedriddenness, and muscle loss. Sarcopenia may also lead to the further development of hepatic encephalopathy.

[0123] Pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients are disclosed for use in the treatment of sarcopenia. Pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients are also disclosed for use in improving symptoms of sarcopenia.

[0124] i. Pharmaceutical Composition

[0125] In some aspects, a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof may be one or more of those pharmaceutical compositions disclosed herein. In some aspects, the pharmaceutical composition has a multi-matrix structure comprising an amphiphilic matrix incorporating rifamycin SV; a lipophilic matrix formed of a substance having a melting point below 90°C and wherein a) is dispersed; and a hydrophilic matrix.

[0126] In some aspects, the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. In some aspects, the amphiphilic substance may be present in an amount ranging from 0.001% to 0.0500% by weight, or 0.005% to 0.050% by weight, or 0.005% to 0.030% by weight of the composition.

[0127] In some aspects, the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts. In some aspects, the lipophilic substance may be present in an amount ranging from 0.01% to 0.050% by weight, or 0.01% to 0.035% by weight, or 0.015% to 0.025% by weight of the composition.

[0128] In some aspects, the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol. In some aspects, the hydrophilic substance may be present in an amount ranging from 0.05% to 0.50% by weight, or 0.1% to 0.5% by weight, or 0.1% to 0.3% by weight of the composition.

[0129] In some aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing stearic acid, and a hydrophilic matrix containing sodium carboxymethyl cellulose. In other aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing glyceryl distearate, and a hydrophilic matrix of ammonium methacrylate copolymer (type B).

[0130] In some aspects, the pharmaceutical composition further comprises a gastric-tolerant (or enteric) coating. In some aspects, the pharmaceutical composition may comprise a gastric-tolerant coating dissolved at a pH of about 5, or about 5.5, or about 6.0, or about 6.2, or about 6.4, or about 6.6, or about 6.8, or about 7.0, or about 7.1, or about 7.2. In some aspects, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.4. In another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.8. In yet another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 7.2. In some aspects, the gastric-tolerant coating may comprise shellac, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose succinate acetate. In other respects, the gastric-resistant coating (film) covering the tablet core may contain polymethacrylate, acrylic acid and / or methacrylate polymers or copolymers, or cellulose derivatives such as cellulose acetylated phthalate. Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L). Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (e.g., commercially known as EUDRAGITS). Optionally, the gastric-resistant coating comprises a methacrylate-ethyl acrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L30 D55). Optionally, the gastric-resistant coating comprises a polymethacrylate copolymer, including but not limited to compounds and / or mixtures thereof commercially known as EUDRAGIT S (methacrylate-methyl methacrylate copolymer 1:2), EUDRAGIT L (methacrylate-methyl methacrylate 1:1 copolymer), and / or EUDRAGIT L30 D55 (methacrylate-ethyl acrylate 1:1 copolymer). The gastric tolerance coating may comprise a methacrylate-(meth)acrylate copolymer. In some embodiments, the gastric tolerance coating comprises a methacrylate / methyl methacrylate copolymer.

[0131] Gastric tolerance coatings may contain methacrylic acid / methyl methacrylate (1:1) copolymer (EUDRAGIT L) or methacrylic acid / methyl methacrylate (1:2) copolymer (EUDRAGIT S).

[0132] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (EUDRAGITL).

[0133] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (EUDRAGITS).

[0134] In some embodiments, the gastric tolerance coating comprises a mixture of a 1:1 copolymer of methacrylic acid and a 1:2 copolymer of methacrylic acid and methyl methacrylate. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 0.5:1 to 3:1. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 1:1 to 3:1. In some embodiments, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of about 2:1.

[0135] Optionally, a unit dose of the gastric tolerance coating begins to rupture or dissolve at a pH of 5 or higher, optionally at a pH of about 6 or higher, at a pH of 6.5 or higher, or at a pH of 6.8. In some embodiments, the active substance is released from the tablet core at a pH of at least 5, such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, the active substance is released from the tablet core at a pH in the range of about 6.5 to about 7.5, optionally in the range of about 6.8 to about 7. According to one aspect, the active ingredient is released from the tablet core at pH 6.8. According to another aspect, the active ingredient is released from the tablet core at pH 7. According to a further aspect, the active ingredient is released from the tablet core at pH 7.2.

[0136] In some aspects, the pharmaceutical composition comprises a tablet core and a coating covering said core. In some aspects, the coating may be a gastric-tolerant coating, a delayed-release coating, or a prolonged-release coating.

[0137] In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum).

[0138] In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine (duodenum, jejunum, and ileum)) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum) and optionally continues throughout the large intestine.

[0139] In some respects, the pharmaceutical composition is suitable for any known administration, particularly those described herein. In some respects, the pharmaceutical composition is suitable for oral administration. In other respects, the pharmaceutical composition is suitable for rectal administration. In a further respect, the pharmaceutical composition is suitable for parenteral administration, including intravenous, intramuscular, or subcutaneous injection. In a preferred respect, the pharmaceutical composition is suitable for oral administration.

[0140] This document discloses a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients for the treatment of sarcopenia, wherein the pharmaceutical composition has a multi-matrix structure comprising: a) an amphiphilic matrix incorporating rifamycin SV; b) a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the lipophilic matrix of a) is dispersed; and c) a hydrophilic matrix; wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers; wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated... The pharmaceutical composition comprises: ethanol or fatty acids, their salts or esters; monoglycerides, diglycerides or triglycerides of fatty acids or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts; wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxyalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol or mannitol; wherein the pharmaceutical composition further comprises a gastric-tolerant coating; wherein the pharmaceutical composition comprises a tablet core and a coating covering the core; and wherein the pharmaceutical composition is suitable for oral administration.This document discloses a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients for use in improving symptoms of sarcopenia, wherein the pharmaceutical composition has a multi-matrix structure comprising: a) an amphiphilic matrix incorporating rifamycin SV; b) a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the lipophilic matrix of a) is dispersed; and c) a hydrophilic matrix; wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers; wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or Hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts; wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol or mannitol; wherein the pharmaceutical composition further comprises a gastric-tolerant coating; wherein the pharmaceutical composition comprises a tablet core and a coating covering the core; and wherein the pharmaceutical composition is suitable for oral administration.

[0141] The pharmaceutical compositions used in the methods disclosed herein for treating subjects with sarcopenia or improving sarcopenia symptoms in subjects with sarcopenia may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 1,100 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may contain about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0142] In some aspects, the pharmaceutical compositions used in the methods disclosed herein for treating subjects with sarcopenia or improving sarcopenia symptoms in subjects with sarcopenia may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In other aspects, the pharmaceutical compositions may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0143] Pharmaceutical compositions for treating or improving sarcopenia symptoms may include administering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating sarcopenia may include administering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia symptoms may include administering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia symptoms may include administering about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia symptoms may include administering about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia symptoms may include administering about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia may include the step of administering about 1,400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia may include the step of administering about 1,600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating or improving sarcopenia may include the step of administering about 1,800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. This can be achieved by administering a single dosage form delivering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. This can be achieved by administering a single dosage form delivering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Preferably, this can be achieved by administering a single dosage form delivering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Advantageously, patient compliance is increased if a single dosage form (such as an oral pharmaceutical composition in solid dosage form) contains about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0144] ii. Treatment

[0145] In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering the pharmaceutical composition to a subject in need once daily. In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering the pharmaceutical composition to a subject in need twice daily. In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering the pharmaceutical composition to a subject in need three times daily. In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering the pharmaceutical composition to a subject in need four times daily.

[0146] In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering a pharmaceutical composition to a subject in need for 15 days, 30 days, 45 days, 2 months, 3 months, 4 months, 5 months, or 6 months. In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms may include administering a pharmaceutical composition to a subject in need for at least 30 days.

[0147] Therefore, one example of a method for treating sarcopenia or improving sarcopenia symptoms involves administering a drug composition twice daily to a subject in need for 30 days.

[0148] iii. Subject population

[0149] In some aspects, methods of treating sarcopenia or improving sarcopenia symptoms include administering a pharmaceutical composition to a subject, wherein the subject suffers from a chronic disease. In some aspects, the chronic disease is selected from the group comprising: cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, and end-stage lung disease. In some aspects, the chronic disease is cirrhosis and / or hepatic encephalopathy.

[0150] In some respects, the subject had been diagnosed with sarcopenia prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0151] In some respects, the subject had been diagnosed with mild hepatic encephalopathy prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0152] In some respects, the subject had been diagnosed with cirrhosis prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0153] In some respects, the subject had been diagnosed with relevant cognitive impairment prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0154] In some respects, the subject did not have diarrhea prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0155] In some respects, the subjects had previously received treatment with lactulose or rifaximin.

[0156] 2. Improve muscle mass

[0157] A method for improving muscle mass in a subject is disclosed, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0158] A pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients is disclosed, said pharmaceutical composition being used to improve muscle mass in a subject.

[0159] i. Pharmaceutical Composition

[0160] In some aspects, a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof may be one or more of those pharmaceutical compositions disclosed herein. In some aspects, the pharmaceutical composition has a multi-matrix structure comprising an amphiphilic matrix incorporating rifamycin SV; a lipophilic matrix formed of a substance having a melting point below 90°C and wherein a) is dispersed; and a hydrophilic matrix.

[0161] In some aspects, the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. In some aspects, the amphiphilic substance may be present in an amount ranging from 0.001% to 0.0500% by weight, or 0.005% to 0.050% by weight, or 0.005% to 0.030% by weight of the composition.

[0162] In some aspects, the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts. In some aspects, the lipophilic substance may be present in an amount ranging from 0.01% to 0.050% by weight, or 0.01% to 0.035% by weight, or 0.015% to 0.025% by weight of the composition.

[0163] In some aspects, the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol. In some aspects, the hydrophilic substance may be present in an amount ranging from 0.05% to 0.50% by weight, or 0.1% to 0.5% by weight, or 0.1% to 0.3% by weight of the composition.

[0164] In some aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing stearic acid, and a hydrophilic matrix containing sodium carboxymethyl cellulose. In other aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing glyceryl distearate, and a hydrophilic matrix of ammonium methacrylate copolymer (type B).

[0165] In some aspects, the pharmaceutical composition further comprises a gastric-tolerant (or enteric) coating. In some aspects, the pharmaceutical composition may comprise a gastric-tolerant coating dissolved at a pH of about 5, or about 5.5, or about 6.0, or about 6.2, or about 6.4, or about 6.6, or about 6.8, or about 7.0, or about 7.1, or about 7.2. In some aspects, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.4. In another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.8. In yet another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 7.2. In some aspects, the gastric-tolerant coating may comprise shellac, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose succinate acetate.

[0166] In other respects, the gastric-resistant coating (film) covering the tablet core may contain polymethacrylate, acrylic acid and / or methacrylate polymers or copolymers, or cellulose derivatives such as cellulose acetylated phthalate. Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L). Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (e.g., commercially known as EUDRAGIT S). Optionally, the gastric-resistant coating comprises a methacrylate-ethyl acrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L30 D55). Optionally, the gastric-resistant coating comprises a polymethacrylate copolymer, including but not limited to compounds and / or mixtures thereof commercially known as EUDRAGIT S (methacrylate-methyl methacrylate copolymer 1:2), EUDRAGIT L (methacrylate-methyl methacrylate 1:1 copolymer), and / or EUDRAGIT L30 D55 (methacrylate-ethyl acrylate 1:1 copolymer). The gastric tolerance coating may comprise a methacrylate-(meth)acrylate copolymer. In some embodiments, the gastric tolerance coating comprises a methacrylate / methyl methacrylate copolymer.

[0167] Gastric tolerance coatings may contain methacrylic acid / methyl methacrylate (1:1) copolymer (EUDRAGIT L) or methacrylic acid / methyl methacrylate (1:2) copolymer (EUDRAGIT S).

[0168] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (EUDRAGITL).

[0169] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (EUDRAGITS).

[0170] In some embodiments, the gastric tolerance coating comprises a mixture of a 1:1 copolymer of methacrylic acid and a 1:2 copolymer of methacrylic acid and methyl methacrylate. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 0.5:1 to 3:1. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 1:1 to 3:1. In some embodiments, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of about 2:1.

[0171] Optionally, a unit dose of the gastric tolerance coating begins to rupture or dissolve at a pH of 5 or higher, optionally at a pH of about 6 or higher, at a pH of 6.5 or higher, or at a pH of 6.8. In some embodiments, the active substance is released from the tablet core at a pH of at least 5, such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, the active substance is released from the tablet core at a pH in the range of about 6.5 to about 7.5, optionally in the range of about 6.8 to about 7. According to one aspect, the active ingredient is released from the tablet core at pH 6.8. According to another aspect, the active ingredient is released from the tablet core at pH 7. According to a further aspect, the active ingredient is released from the tablet core at pH 7.2.

[0172] In some aspects, the pharmaceutical composition comprises a tablet core and a coating covering said core. In some aspects, the coating may be a gastric-tolerant coating, a delayed-release coating, or a prolonged-release coating.

[0173] In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum).

[0174] In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine (duodenum, jejunum, and ileum)) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum) and optionally continues throughout the large intestine.

[0175] In some respects, the pharmaceutical composition is suitable for any known administration, particularly those described herein. In some respects, the pharmaceutical composition is suitable for oral administration. In other respects, the pharmaceutical composition is suitable for rectal administration. In a further respect, the pharmaceutical composition is suitable for parenteral administration, including intravenous, intramuscular, or subcutaneous injection. In a preferred respect, the pharmaceutical composition is suitable for oral administration.

[0176] This document discloses a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients for the treatment of sarcopenia, wherein the pharmaceutical composition has a multi-matrix structure comprising: a) an amphiphilic matrix incorporating rifamycin SV; b) a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the lipophilic matrix of a) is dispersed; and c) a hydrophilic matrix; wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers; wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated... The pharmaceutical composition comprises: ethanol or fatty acids, their salts or esters; monoglycerides, diglycerides or triglycerides of fatty acids or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts; wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxyalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol or mannitol; wherein the pharmaceutical composition further comprises a gastric-tolerant coating; wherein the pharmaceutical composition comprises a tablet core and a coating covering the core; and wherein the pharmaceutical composition is suitable for oral administration.

[0177] In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 1,100 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0178] In some aspects, the pharmaceutical composition used in methods for improving muscle mass may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In another aspect, the pharmaceutical composition used in methods for improving muscle mass may contain about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In yet another aspect, the pharmaceutical composition used in methods for improving muscle mass may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0179] Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 1,400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 1,600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for improving muscle mass in subjects may include the step of administering about 1,800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. This can be achieved by administering a single dosage form delivering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. This can be achieved by administering a single dosage form delivering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Preferably, this can be achieved by administering a single dosage form delivering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Advantageously, patient compliance is increased if a single dosage form (such as an oral pharmaceutical composition in solid dosage form) contains about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0180] ii. Treatment

[0181] In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to the subject in need once daily. In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to the subject in need twice daily. In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to the subject in need three times daily. In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to the subject in need four times daily.

[0182] In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to a subject in need for 15 days, 30 days, 45 days, 2 months, 3 months, 4 months, 5 months, or 6 months. In some aspects, methods for improving muscle mass in a subject may include administering the pharmaceutical composition to a subject in need for at least 30 days.

[0183] Therefore, one example of a method to improve muscle mass in subjects involves administering a drug composition twice daily to subjects in need for 30 days.

[0184] iii. Subject population

[0185] In some aspects, methods for improving muscle mass in a subject include administering a pharmaceutical composition to the subject, wherein the subject suffers from a chronic disease. In some aspects, the chronic disease is selected from the group comprising: cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, and end-stage lung disease. In some aspects, the chronic disease is cirrhosis and / or hepatic encephalopathy.

[0186] In some respects, the subject had been diagnosed with sarcopenia prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0187] In some respects, the subject had been diagnosed with mild hepatic encephalopathy prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0188] In some respects, the subject had been diagnosed with cirrhosis prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0189] In some respects, the subject had been diagnosed with relevant cognitive impairment prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0190] In some respects, the subject did not have diarrhea prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0191] In some respects, the subjects had previously received treatment with lactulose or rifaximin.

[0192] 3. Treatment of cirrhosis

[0193] A method for treating a subject with cirrhosis is disclosed, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0194] Pharmaceutical compositions comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients, are disclosed for use in the treatment of cirrhosis.

[0195] i. Pharmaceutical Composition

[0196] In some aspects, a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof may be one or more of those pharmaceutical compositions disclosed herein. In some aspects, the pharmaceutical composition has a multi-matrix structure comprising an amphiphilic matrix incorporating rifamycin SV; a lipophilic matrix formed of a substance having a melting point below 90°C and wherein a) is dispersed; and a hydrophilic matrix.

[0197] In some aspects, the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, and / or ethylene and / or propylene block copolymers. In some aspects, the amphiphilic substance may be present in an amount ranging from 0.001% to 0.0500% by weight, or 0.005% to 0.050% by weight, or 0.005% to 0.030% by weight of the composition.

[0198] In some aspects, the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts. In some aspects, the lipophilic substance may be present in an amount ranging from 0.01% to 0.050% by weight, or 0.01% to 0.035% by weight, or 0.015% to 0.025% by weight of the composition.

[0199] In some aspects, the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol. In some aspects, the hydrophilic substance may be present in an amount ranging from 0.05% to 0.50% by weight, or 0.1% to 0.5% by weight, or 0.1% to 0.3% by weight of the composition.

[0200] In some aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing stearic acid, and a hydrophilic matrix containing sodium carboxymethyl cellulose. In other aspects, the pharmaceutical composition may comprise an amphiphilic matrix containing lecithin, a lipophilic matrix containing glyceryl distearate, and a hydrophilic matrix of ammonium methacrylate copolymer (type B).

[0201] In some aspects, the pharmaceutical composition further comprises a gastric-tolerant (or enteric) coating. In some aspects, the pharmaceutical composition may comprise a gastric-tolerant coating dissolved at a pH of about 5, or about 5.5, or about 6.0, or about 6.2, or about 6.4, or about 6.6, or about 6.8, or about 7.0, or about 7.1, or about 7.2. In some aspects, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.4. In another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 6.8. In yet another preferred embodiment, the pharmaceutical composition comprises a gastric-tolerant coating dissolved at a pH of about 7.2. In some aspects, the gastric-tolerant coating may comprise shellac, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose succinate acetate. In other respects, the gastric-resistant coating (film) covering the tablet core may contain polymethacrylate, acrylic acid and / or methacrylate polymers or copolymers, or cellulose derivatives such as cellulose acetylated phthalate. Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L). Optionally, the gastric-resistant coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (e.g., commercially known as EUDRAGITS). Optionally, the gastric-resistant coating comprises a methacrylate-ethyl acrylate (1:1) copolymer (e.g., commercially known as EUDRAGIT L30 D55). Optionally, the gastric-resistant coating comprises a polymethacrylate copolymer, including but not limited to compounds and / or mixtures thereof commercially known as EUDRAGIT S (methacrylate-methyl methacrylate copolymer 1:2), EUDRAGIT L (methacrylate-methyl methacrylate 1:1 copolymer), and / or EUDRAGIT L30 D55 (methacrylate-ethyl acrylate 1:1 copolymer). The gastric tolerance coating may comprise a methacrylate-(meth)acrylate copolymer. In some embodiments, the gastric tolerance coating comprises a methacrylate / methyl methacrylate copolymer.

[0202] Gastric tolerance coatings may contain methacrylic acid / methyl methacrylate (1:1) copolymer (EUDRAGIT L) or methacrylic acid / methyl methacrylate (1:2) copolymer (EUDRAGIT S).

[0203] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:1) copolymer (EUDRAGITL).

[0204] Optionally, the gastric tolerance coating comprises a methacrylate / methyl methacrylate (1:2) copolymer (EUDRAGITS).

[0205] In some embodiments, the gastric tolerance coating comprises a mixture of a 1:1 copolymer of methacrylic acid and a 1:2 copolymer of methacrylic acid and methyl methacrylate. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 0.5:1 to 3:1. Optionally, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of 1:1 to 3:1. In some embodiments, the mixture comprises a 1:1 copolymer of methacrylic acid and methyl methacrylate (1:2) in a weight ratio of about 2:1.

[0206] Optionally, a unit dose of the gastric tolerance coating begins to rupture or dissolve at a pH of 5 or higher, optionally at a pH of about 6 or higher, at a pH of 6.5 or higher, or at a pH of 6.8.

[00206] In some embodiments, the active substance is released from the tablet core at a pH of at least 5, such as 5.1, or 5.2, or 5.3, or 5.4, or 5.5, or 5.6, or 5.7, or 5.8, or 5.9, or 6, or 6.1, or 6.2, or 6.3, or 6.4, or 6.5, or 6.6, or 6.7, or 6.8, or 6.9, or 7, or 7.1, or 7.2, or 7.3, or 7.4, or 7.5. In some embodiments, the active substance is released from the tablet core at a pH in the range of about 6.5 to about 7.5, optionally at a pH in the range of about 6.8 to about 7. According to one aspect, the active ingredient is released from the tablet core at pH 6.8. According to another aspect, the active ingredient is released from the tablet core at pH 7. According to a further aspect, the active ingredient is released from the tablet core at pH 7.2.

[0207] In some aspects, the pharmaceutical composition comprises a tablet core and a coating covering said core. In some aspects, the coating may be a gastric-tolerant coating, a delayed-release coating, or a prolonged-release coating. In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum). In some aspects, the pharmaceutical composition may be formulated for delayed release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum).

[0208] In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the intestine (i.e., in the small intestine (duodenum, jejunum, and ileum)) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the distal portion of the small intestine (e.g., in the ileum) and optionally continues throughout the large intestine. In some aspects, the pharmaceutical composition can be formulated for prolonged release, such that the release of rifamycin SV or a pharmaceutically acceptable salt thereof begins in the proximal portion of the colon (e.g., in the cecum) and optionally continues throughout the large intestine.

[0209] In some respects, the pharmaceutical composition is suitable for any known administration, particularly those described herein. In some respects, the pharmaceutical composition is suitable for oral administration. In other respects, the pharmaceutical composition is suitable for rectal administration. In a further respect, the pharmaceutical composition is suitable for parenteral administration, including intravenous, intramuscular, or subcutaneous injection. In a preferred respect, the pharmaceutical composition is suitable for oral administration.

[0210] This document discloses a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients for the treatment of sarcopenia, wherein the pharmaceutical composition has a multi-matrix structure comprising: a) an amphiphilic matrix incorporating rifamycin SV; b) a lipophilic matrix formed of a substance having a melting point below 90°C and wherein the lipophilic matrix of a) is dispersed; and c) a hydrophilic matrix; wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelins, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers; wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated... The pharmaceutical composition comprises: ethanol or fatty acids, their salts or esters; monoglycerides, diglycerides or triglycerides of fatty acids or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts; wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxyalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol or mannitol; wherein the pharmaceutical composition further comprises a gastric-tolerant coating; wherein the pharmaceutical composition comprises a tablet core and a coating covering the core; and wherein the pharmaceutical composition is suitable for oral administration.

[0211] In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 1,100 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in a method of treating a subject with cirrhosis may contain about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0212] In some aspects, the pharmaceutical composition used in methods of treating subjects with cirrhosis may contain about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition used in methods of treating subjects with cirrhosis may contain about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0213] Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 1,000 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 1,200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 1,400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 1,600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. Pharmaceutical compositions for treating subjects with cirrhosis may include the step of administering about 1,800 mg of rifamycin SV or a pharmaceutically acceptable salt thereof to a subject in need. This can be achieved by administering a single dosage form delivering about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. This can be achieved by administering a single dosage form delivering about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 400 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Preferably, this can be achieved by administering a single dosage form delivering about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof, or by administering multiple dosage forms to deliver a total dose of about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof. Advantageously, patient compliance is increased if a single dosage form (such as an oral pharmaceutical composition in solid dosage form) contains about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

[0214] ii. Treatment

[0215] In some aspects, methods of treating a subject with cirrhosis may include administering the pharmaceutical composition to the subject in need once daily. In some aspects, methods of treating a subject with cirrhosis may include administering the pharmaceutical composition to the subject in need twice daily. In some aspects, methods of treating a subject with cirrhosis may include administering the pharmaceutical composition to the subject in need three times daily. In some aspects, methods of treating a subject with cirrhosis may include administering the pharmaceutical composition to the subject in need four times daily.

[0216] In some aspects, treatment of a subject with cirrhosis may include administering the drug composition to the subject in need for 15 days, 30 days, 45 days, 2 months, 3 months, 4 months, 5 months, or 6 months. In some aspects, treatment may include administering the drug composition to the subject in need for at least 30 days.

[0217] Therefore, one example of treatment involves administering the drug composition to the subject in need twice daily for 30 days.

[0218] iii. Subject population

[0219] In some aspects, methods of treating a subject with cirrhosis include administering a pharmaceutical composition to the subject, wherein the subject suffers from a chronic disease. In some aspects, the chronic disease is selected from the group comprising: cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, and end-stage lung disease. In some aspects, the chronic disease is cirrhosis and / or hepatic encephalopathy.

[0220] In some respects, the subject had been diagnosed with sarcopenia prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0221] In some respects, the subject had been diagnosed with mild hepatic encephalopathy prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0222] In some respects, the subject had been diagnosed with cirrhosis prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0223] In some respects, the subject had been diagnosed with relevant cognitive impairment prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0224] In some respects, the subject did not have diarrhea prior to administration of a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients.

[0225] In some respects, the subjects had previously received treatment with lactulose or rifaximin.

[0226] D. Combination therapy

[0227] In one aspect of the disclosed method, the pharmaceutical composition may be administered alone or in combination with one or more additional therapeutic agents. The additional therapeutic agent is selected based on the disease or symptom to be treated. Descriptions of suitable pharmacological agents and drugs of various types can be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (11th edition, McGraw-Hill Publishing Co.) (2005). For example, the disclosed method may be a combination therapy using a pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and androgen derivatives, bile acid analogs, lactulose, beta-blockers, other antibiotics, fecal microbiota grafts, or diuretics.

[0228] E. Reagent kit

[0229] The above-described compositions and materials, along with other materials, can be packaged together in any suitable combination as a kit for performing or assisting in the performance of the disclosed methods. It is useful if the kit components in a given kit are designed and suitable for use in the disclosed methods.

[0230] Example

[0231] A. Example 1

[0232] 1. Introduction

[0233] Minimal hepatic encephalopathy (MHE) is associated with adverse outcomes, but treatment strategies are limited. Rifamycin SV MMX (RiVM) is a novel rifamycin SV composition containing an antibiotic formulated in a delayed and / or extended-release formulation to provide optimal release and concentration of the active substance in the colon. Purpose : To evaluate the effects of RiVM on the microbiome, safety, and gut-brain axis in an RCT.

[0234] In a randomized, double-blind, placebo-controlled clinical trial, rifamycin SV MMX (RIVM) was deemed safe and beneficial in altering the composition and function of the gut microbiota in patients with mild hepatic encephalopathy (MHE) compared to placebo. The aim was to determine the safety and tolerability of RIVM in patients with cirrhosis and MHE. The primary outcome was changes in the fecal cirrhotic dysbiosis ratio (CDR) and microbiome composition. Secondary outcomes included safety and tolerability, effects on cognitive tests, microbial function, fecal calprotectin, patient-reported outcomes, sarcopenia, and changes in salivary microbiota.

[0235] Exemplary rifamycin SV MMX compositions containing 600 mg rifamycin SV are disclosed in the table below:

[0236] Table 1

[0237]

[0238] (1) As an anhydrous substance (dried), considering an average water content of about 14.5%, it is equivalent to about 702 mg of rifamycin SV sodium salt in hydrate form.

[0239] (2) Adjust the amount of mannitol to compensate for the rifamycin SV sodium amount correction based on the water content.

[0240] (3) Purified water and ethanol are essentially removed during manufacturing.

[0241] Rifamycin SV (sodium salt), ascorbic acid, lecithin, stearic acid, and a portion of magnesium stearate were mixed in a suitable container until a homogeneous dispersion was obtained. Mannitol, sodium carboxymethyl cellulose, and silica were then added, and the mixture was stirred again. After the magnesium stearate was added, the powder was compressed in a rotary tablet press to obtain the tablet core. These tablet cores were then coated in a coating pan using ethanol as a solvent with Eudragit L100, triethyl citrate, talc, titanium dioxide, and iron oxide red to apply a gastric-resistant coating layer. The tablets were then polished by adding some polyethylene glycol 6000 to an aqueous solution.

[0242] Another sample composition of the present invention is provided below, namely a representative rifamycin SV MMX composition containing 600 mg of rifamycin SV:

[0243] Table 2

[0244]

[0245] (1) As an anhydrous substance (dried), considering an average water content of about 14.5%, it is equivalent to about 702 mg of rifamycin SV sodium salt in hydrate form.

[0246] (2) Adjust the amount of mannitol to compensate for the rifamycin SV sodium amount correction based on the water content.

[0247] (3) Purified water and ethanol are essentially removed during manufacturing.

[0248] Rifamycin SV (sodium salt), ascorbic acid, lecithin, stearic acid, and a portion of magnesium stearate were mixed in a suitable container until a homogeneous dispersion was obtained. Mannitol, sodium carboxymethyl cellulose, and silica were then added, and the mixture was stirred again. Once the magnesium stearate was added, the powder was compressed in a rotary tablet press to obtain the tablet core. These tablet cores were then coated in a coating pan using ethanol as a solvent with a 1:1 mixture of Eudragit S100 and Eudragit L100, triethyl citrate, talc, titanium dioxide, and iron oxide red to apply a gastric-resistant coating. The tablets were then polished by adding some polyethylene glycol 6000 to an aqueous solution.

[0249] The table below describes another example composition according to the invention, a representative rifamycin SV MMX composition containing 200 mg rifamycin SV for the treatment of sarcopenia:

[0250] Table 3

[0251]

[0252] (1) Based on anhydrous; the amount is adjusted based on the water content and purity of rifamycin sodium.

[0253] (2) Adjustments were made based on the water content and purity of rifamycin sodium.

[0254] (3) The alcohol (ethanol) and purified water used during the film coating and polishing steps are substantially removed during the manufacturing process.

[0255] Since the above formulation contains 200 mg of rifamycin SV, three tablets can be administered to achieve a dose of approximately 600 mg of rifamycin SV.

[0256] 2. Methods

[0257] This is a randomized, double-blind, placebo-controlled clinical trial in which participants were cirrhotic patients who received 30 days of treatment and then stopped treatment for 7 days. The trial was conducted under FDA research authorization.

[0258] i. Subject population:

[0259] The study population consisted of patients aged 18–75 years with cirrhosis who were able to consent but had cognitive impairment in PHES or Encephal Applied Stroop. Diagnosis of cirrhosis was made by liver biopsy, or imaging features of a nodular liver with varices, endoscopic varices, or a platelet count <150,000 and AST / ALT >1 in patients with chronic liver disease. Patients were required to have stable liver function for 2–12 weeks prior to enrollment, and those of childbearing age must have been practicing reliable contraception. Patients were excluded if they had any of the following: an unclear diagnosis of cirrhosis, a history / current overt hepatitis B (HE), rifaximin or lactulose therapy, unstable liver-related enzymes, recent (<3 months) alcohol / illegal drug use, advanced liver disease (Children's disease score >8, MELD >20, Na <125), antibiotic use within 6 weeks, use of psychoactive drugs in addition to long-term opioid use or stable use of antidepressants, recent (<1 month) infection, post-transplant status, allergic reactions to rifamycin, rifampin, or rifaximin derivatives, end-stage organ failure (CHF with EF <25%, end-stage renal disease requiring dialysis, COPD requiring home oxygen therapy), if using statins, the duration of statin therapy was <3 months, and patients unlikely to survive 6 weeks or maintain 6 weeks without liver transplantation, or patients unable to adhere to trial-related activities.

[0260] ii. Overall research process:

[0261] Once potential participants signed informed consent, screening activities were performed, including MMSE for all participants, cognitive tests (PHES, EncephalApp Stroop), and urine pregnancy tests for women of childbearing age. Patients with MMSE <25, patients with normal results compared to US standards for EncephalApp and PHES, and pregnant patients were excluded. The remaining patients were eligible for randomization, and the remaining study activities, such as... Figure 1A As shown.

[0262] iii. Random grouping:

[0263] Using sealed envelopes stored in the study pharmacy, participants were randomly assigned in a 1:1 ratio to receive either oral rifamycin-SV MMX 600 mg PO twice daily (total 1,200 mg daily) or placebo for 30 days, followed by a 7-day follow-up period after discontinuation of treatment. Only the study pharmacist knew the randomization protocol.

[0264] iv. Security assessment:

[0265] During each visit, a physical examination, medical history taking, and routine safety laboratory tests were performed, including creatine phosphokinase (CPK) testing. Adverse events were thoroughly investigated, as were infections, new cirrhotic complications (overt hepatitis B, variceal bleeding, hospitalizations for liver-related conditions), and any hospitalizations.

[0266] v. Result:

[0267] The primary outcome was the change in the cirrhotic microbiota dysbiosis ratio (CDR), calculated as [Lachnospiraceae + Ruminococaceae + Clostridium Cluster XIV + Veillonellaceae / Enterobacteriaceae + Bacteroidaceae] in feces. Secondary outcomes included (a) the overall microbiota composition in feces and saliva, (b) microbiota function (bile acids and SCFA in feces and metabolomics in serum and urine), (c) fecal calprotectin, (d) cognitive function: PHES, EncephalApp Stroop, (e) HRQOL (Disease Impact Scale) and sleep (PSQI), and (f) a safety assessment of changes in MELD scores and AE / SAE. Exploratory results were associated with sarcopenia, as well as grip strength, InBody assessment, and brain MR spectroscopy in a subset of patients who consented and did not have contraindications to undergo MRI.

[0268] vi. Sample handling and storage:

[0269] Blood samples were sent for routine testing (MELD score, safety), and serum was stored for metabolomics, bile acid profiling, systemic inflammation, and endotoxemia assessment. Midstream urine was collected for metabolomics and stored at -80°C until metabolomics analysis was performed. Naturally excreted feces were collected using the ParaPak kit and aliquoted for microbiome composition and bile acid analysis. Saliva was collected after rinsing the mouth with saline in the presence of a coordinator. This rinse was discarded, and subsequently collected saliva was rapidly frozen for microbiome analysis.

[0270] vii. Safety blood test:

[0271] During each visit, serum basal metabolic rate, liver function, complete blood cell count, serum albumin, venous ammonia, INR, and CPK can be checked.

[0272] viii. Cognitive function:

[0273] Cognitive function was assessed using the validated psychometric Hepatic Encephalopathy Scale (HECS) and the EncephalApp Stroop test. Impairment in any of these measures compared to US standards was considered MHE.

[0274] ix. HRQOL:

[0275] The Disease Impact Scale and the Pittsburgh Sleep Quality Index (PSQI) were applied. The Disease Impact Scale is a validated 136-question HRQOL scale with 12 dimensions that produces an overall score, a physical score, and a psychosocial score.

[0276] x. Inflammation and endotoxemia:

[0277] Serum endotoxin-binding proteins and inflammatory cytokines (IL-6, TNF-α, IL-1β) and fecal calprotectin were analyzed using published ELISA techniques.

[0278] xi. Sarcopenia assessment:

[0279] Functional sarcopenia was assessed using grip strength via a Jamar hand grip dynamometer. Fat and muscle distribution were assessed using an InBody machine (Cerritos, CA) to evaluate structure.

[0280] xii. Microbiome analysis:

[0281] Based on previous studies of feces and saliva, 16S rRNA was used to query and characterize the gut microbiome composition and calculate the CDR [16, 17]. SCFA and BA analyses of feces were performed using published techniques to assess the function of the microbiome. Non-targeted metabolites in serum and urine were analyzed using LC / MS technology at Metabolon Inc (Morrisville NC)

[18] .

[0282] xiii. Brain MRI analysis:

[0283] In a subset of subjects who were willing and able to do so, brain MRS were analyzed using a validated LC model to understand changes in the creatine ratios of inositol, choline, Glx, and GABA [19-21].

[0284] xiv. Sample quantity:

[0285] In previous studies, the CDR changed significantly before and after the development of HE, from 1.20 to 0.42; if the SD of these patients is 0.7 and α is 0.8, then at least 14 patients are required in each group.

[0286] xv. Statistical analysis:

[0287] Repeated measures ANOVA will be performed between groups to analyze changes in primary and secondary outcomes. Incremental changes in cognition, HRQOL, and routine laboratory tests (ammonia, MELD) will be compared between groups and correlated with changes in specific biomarkers (inflammation) between groups.

[0288] 3. Results

[0289] 138 patients were considered, of whom 56 met the eligibility criteria. The remainder either had a history / current overt hepatitis B (n=27), were unwilling to participate (n=25), had an unclear diagnosis of cirrhosis (n=19), or had recently consumed alcohol or used illicit drugs (n=11). Of the 56 patients who signed informed consent and underwent screening, 18 failed the screening due to normal cognitive test results. The remaining 30 patients were randomized 1:1 to either rifamycin or placebo. Figure 1B Patients in the rifamycin group were similar to those in the placebo group in terms of age, sex, cause of cirrhosis, and years of education (Table 4). MELD-Na and other liver disease severity indices (excluding ammonia) at enrollment were similar across groups (Table 4). Ammonia levels were significantly higher in the rifamycin group compared to the placebo group.

[0290] Table 4: Baseline Comparison

[0291]

[0292] i. Clinical process:

[0293] Of the 15 patients randomized to rifamycin, none developed a sarcopenic encephalitis (SAE), and 10 had no adverse events (AEs). One patient experienced increased bloating on day 1, which did not require discontinuation of the study drug; another patient experienced increased bowel frequency on day 30; another patient experienced diarrhea, fatigue, and a fall on day 1; and another patient experienced self-limiting positional dizziness. Finally, one patient developed a self-limiting dry cough on day 4, which did not require antibiotics. None of these required discontinuation of the study drug. Of the 15 patients randomized to placebo, 10 did not develop AEs / SAEs. One patient developed an unrelated SAE (admitted for non-cardiac chest pain), one patient developed abdominal distension on day 5 of the study start, one patient complained of diarrhea on day 5 of randomization, one patient developed jaw and neck pain on day 10 of the study start, one patient developed shoulder pain, and one patient experienced elevated CPK levels on day 30, which returned to normal at the day 37 visit. All of these episodes were self-limiting and did not warrant discontinuation or interruption of the study drug.

[0294] No significant changes were found in liver chemistry, MELD score, CPK, or safety laboratory parameters between or within groups.

[0295] At baseline, ammonia levels were higher in the rifamycin group. Intravenous ammonia was significantly reduced in the rifamycin group compared to baseline and placebo. The increase in ammonia in rifamycin was also greater than in placebo, and this effect was observed in repeated measures analysis (Figure 4).

[0296] ii. Changes in microbiome structure:

[0297] a. Fecal microbiome:

[0298] (A) CDR changes:

[0299] Following rifamycin administration, *Trichophyton* and *Ruminocytaceae* families decreased, while *Bacteroidetes* and the relatively similar *Veillonococci* and *Enterobacteria* families increased. This resulted in a lower CDR compared to baseline with rifamycin and after placebo. Pre- and post-placebo CDRs remained statistically similar. Figures 2A-2B ).

[0300] (B) Diversity:

[0301] At baseline, there were no differences in α-diversity among the groups, but at the end of rifamycin treatment, α-diversity was significantly reduced compared to baseline and after placebo. No changes in α-diversity parameters were observed before and after placebo. Similarly, after rifamycin treatment, significant separation was observed in the PERMANOVA of β-diversity analysis compared to baseline and after placebo, but there was no change before / after placebo treatment. On LEfSe, after rifamycin administration, compared to baseline, Bifidobacterium and Coprobacillus species were significantly increased, but Streptococcus and several genera belonging to the Trichophyceae and Ruminaceae families were decreased (Figure 2). When comparing placebo and rifamycin final values, compared with placebo, rifamycin administration resulted in higher levels of Bacteroides, Coprobacillus, Butyriciococcus, Clostridium XIVa, and Escherichia / Shigella, while lower levels of several members of Ruminaceae and Trichophytonceae, as well as Streptococcus, Barnesiella, Holdemania, and Allprevotella.

[0302] b. Saliva microbiota:

[0303] No changes in α / β diversity or LEfSe were observed within or between groups.

[0304] c. Microbial function (metabolic tracts, SCFAs, and bile acids):

[0305] (A) Fecal SCFA:

[0306] Following rifamycin administration, acetate, propionate, butyrate, isobutyrate, isovalerate, and valerate levels were higher than baseline (Table 5 and Figure 4). No changes were observed in hexanoic acid or branched SCFAs. No changes were observed within or between the placebo and rifamycin groups (Table 5).

[0307] (B) Bile acids:

[0308] In serum and urinary metabolomics, 7-α-dehydrobiose secondary bile acids (BAs) were significantly increased after rifamycin administration compared to placebo and baseline, but concentrations of other BAs, such as porcine cholic acid and ursodeoxycholic acid (UDCA), were also higher. A similar pattern was observed in feces using quantitative LC / MS analysis of BAs (Table 5). Serum C4 levels, indicating total bile acid production, did not change between / within groups.

[0309] Other changes observed in metabolomics are shown in the supplementary table, but as noted above, the main changes were related to bile acids, and some changes were also observed in androgen steroids. Following rifaximin use, sulfated androgens (mostly in an inactive state) decreased compared to baseline and after placebo administration.

[0310] Table 5: Determination of Microbial Structure and Function

[0311]

[0312] Bold text indicates significant differences.

[0313] iii. Patient-reported outcomes, sarcopenia, and grip strength:

[0314] Compared to baseline, there was no change in overall or psychological SIP in the rifamycin group, but significant improvements in physical aspects of SIP were observed (Table 6). Lean body mass as measured by the InBody machine was significantly increased in the rifamycin group compared to baseline, but not in the placebo group. No other changes in InBody measurements (i.e., water, fat mass, etc.) were observed between / within groups. Grip strength was also improved in the rifamycin group compared to baseline, but not in the placebo group.

[0315] Regarding improvements in body SIP, lean body mass, and grip strength, the intragroup increments (changes before and after) were significantly higher in the rifamycin group (Table 7, Figure 4).

[0316] Table 6: Between-group and within-group changes at baseline and study endpoint (*: within-group p<0.05, †: between-group baseline p<0.05, ‡: between-group study endpoint p<0.05). Bold text indicates significant differences.

[0317]

[0318] iii. Cognitive Test:

[0319] Apart from a significant improvement (reduction) in the continuous dotting test, no significant differences were found in the total PHES score or any of the individual components (Table 6). Similarly, no significant changes were observed in the EncephalApp Stroop parameter between or within groups (Table 7). Interestingly, continuous dotting is a test that primarily assesses psychomotor speed.

[0320] Table 7: Differences in changes from baseline to study endpoint between the two groups

[0321]

[0322] B. Example 2

[0323] Sarcopenia and altered muscle function are major problems in patients with cirrhosis and chronic liver disease. While previous animal and cross-sectional studies have demonstrated that changes in gut microbiota composition in cirrhosis are associated with this outcome, human studies are lacking. Gaining gut-based benefits to improve muscle and overall health in cirrhosis has not been previously established in human disease. Using the gut-based antibiotic rifamycin SV MMX, significant improvements relative to baseline were observed in subjects randomized to rifamycin instead of placebo in the following areas: (1) lean body mass; (2) continuous dot test, which is primarily dependent on muscle function; (3) grip strength; and (4) physical aspects of the Disease Impact Scale. These findings demonstrate novel structural and functional changes in physical function and muscle mass in these patients. These changes have not been observed in other test drugs such as rifaximin, fecal microbiota transplantation, or albumin.

[0324] Rifamycin SV MMX combinations can be used to beneficially improve muscle mass, alleviate sarcopenia, and improve physical function in patients with cirrhosis and other chronic diseases. These may include, but are not limited to, cancer cachexia, chronic renal failure, congestive heart failure, and end-stage lung disease. Other conditions may focus on muscle disorders and emaciation in patients requiring rehabilitation.

[0325] Cirrhosis can lead to scarring and a variety of complications, partly due to problems with the gut microbiome. This is associated with poor muscle structure and function, which in turn is linked to falls and brain problems. Rifamycin SV MMX is an antibiotic that remains primarily in the gut and can affect these microbes. A 30-day trial was conducted on patients with cirrhosis, with half receiving rifamycin and the other half receiving an inactive placebo, and the starting treatment was unknown. Lean body mass improved only in the rifamycin group. Furthermore, this was found to be associated with improvements in grip strength and brain function tests assessing muscle function in the rifamycin group. Finally, from a physical function perspective, patients taking rifamycin also felt better than at baseline. These changes are related to the gut microbiome and its function. Altering the gut microbiome with rifamycin can improve lean body mass and muscle function in cirrhosis.

[0326] C. Example 3

[0327] 1. Background:

[0328] Minimal hepatic encephalopathy (MHE) is associated with adverse outcomes, but treatment strategies are limited. Rifamycin SV MMX (RiVM) is a novel rifampicin derivative and a non-absorbable antibiotic with the greatest impact on the colon.

[0329] Objective: To evaluate the effects of RiVM on the microbiome, safety, and gut-brain axis in an RCT.

[0330] Methods: A phase 2 placebo-controlled, double-blind randomized controlled trial under an FDA IND. Cirrhotic output patients were randomized 1:1 to RiVM or placebo using the MHE (PHES or Stroop) regimen, receiving 600 mg (1200 mg) twice daily for 30 days, followed by a 7-day follow-up period. Four visits were conducted: baseline, day 7, day 15, and day 30. The primary outcome was changes in fecal microbiota (CDR, high = good) from baseline to day 30 (endpoint) with rifamycin versus placebo, obtained by 16S rRNA sequencing. CDR was the ratio of Trichophyton + Ruminaceae + Veillonaceae to Enterobacteriaceae + Bacteroidetes. Secondary outcomes included gut-brain (cognition, serum ammonia, optional brain MR spectroscopy, MRS), inflammation (fecal calprotectin), PRO (SIP: total, physical, psychosocial, high = worse), and grip strength. Between-group / within-group comparisons and increments (post-test increment minus pre-test increment) were performed.

[0331] 2. Results:

[0332] Fifty-eight patients were screened; eight had dominant hepatic encephalopathy (HE), eleven failed screening because they did not have mesenchymal hepatopathy (MHE) at the time of testing, and nine were not interested. Ultimately, 30 patients were enrolled (n=15 / group), who completed the study without any safety issues, including post-treatment visits, and with good adherence. Baselines were substantially similar across groups, but the ammonia and SIP scores were higher in the RiVM group than in the placebo group (Table 6). Seven RiVM and eleven placebo-assigned patients consented to and were eligible for optional brain MRS.

[0333] microbiome The decrease in CDR in RiVM patients was due to a decrease in Trichophyton + Ruminaceae, but an increase in Bacteroidetes. Clustering after RiVM compared to before RiVM and after RiVM compared to placebo showed decreased α-diversity and significant changes in β-diversity (Figure D / E).

[0334] laboratory MELD-Na remained unchanged, but ammonia and calprotectin decreased in the RiVM group compared to baseline, and the ammonia increment was higher in the RiVM group (Table 6). Figure 5B The placebo showed no change.

[0335] Cognitive and Brain MRS: Although continuous tapping of psychomotor velocity was improved in the RiVM, no other changes were observed within / between groups. In brain MRS, glutathione levels were increased in the RiVM group and decreased in the placebo group (p=0.03), but other metabolites (choline, inositol, glutamate / glutamine) remained similar. PRO Compared to the placebo, RiVM showed higher SIP and grip strength increments, indicating improved strength and better body QOL.

[0336] Conclusion: No safety issues were observed in this phase 2, double-blind, placebo-controlled RCT of rifamycin SV MMX in patients with cirrhosis and mesenteric endocrine disorders (MHE). RiVM Rx resulted in reduced gut microbiota alpha diversity and a lower rate of dysbiosis in patients with cirrhosis. RiVM therapy was associated with reduced blood ammonia levels and improvements in physical function and grip strength. RiVM also reduced oxidative stress in the brain, but cognitive tests showed no change. RiCM, with its major colonic effects, may play an important role in the gut-brain axis regulation of cirrhosis and MHE.

[0337] Those skilled in the art will recognize, or be able to determine, many equivalents of specific embodiments of the methods and compositions described herein using only conventional experiments. Such equivalents are contemplated for coverage by the following claims.

Claims

1. A pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof, and one or more carriers and / or excipients, said pharmaceutical composition for the treatment of sarcopenia.

2. The pharmaceutical composition according to claim 1, having a multi-matrix structure, said multi-matrix structure comprising: a. It incorporates an amphiphilic matrix containing rifamycin SV; b. Formed from a substance with a melting point below 90°C and wherein a) is dispersed a lipophilic matrix; and c. Hydrophilic matrix.

3. The pharmaceutical composition according to claim 2, wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelin, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers.

4. The pharmaceutical composition according to claim 2 or 3, wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol.

6. The pharmaceutical composition used according to any of the preceding claims, wherein the composition further comprises a gastric-tolerant coating.

7. The pharmaceutical composition used according to any of the preceding claims, wherein the composition comprises a tablet core and a coating covering the core.

8. The pharmaceutical composition used according to any one of the preceding claims, wherein the composition is suitable for oral administration.

9. The pharmaceutical composition used according to any one of the preceding claims, wherein the composition comprises at least about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition used according to any one of the preceding claims, wherein the composition comprises about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for treating sarcopenia, wherein the treatment comprises administering about 600 mg of rifamycin SC or a pharmaceutically acceptable salt thereof to a subject in need.

12. The pharmaceutical composition used according to any of the preceding claims, wherein the subject suffers from a chronic disease.

13. The pharmaceutical composition according to claim 11, wherein the chronic disease is selected from the group consisting of: cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, and end-stage lung disease.

14. The pharmaceutical composition according to any of claims 11 or 12, wherein the chronic disease is cirrhosis and / or hepatic encephalopathy.

15. The pharmaceutical composition according to any of the preceding claims, wherein the treatment comprises administering the composition to the subject in need twice daily.

16. The pharmaceutical composition of claim 14, wherein the treatment comprises administering the composition to the subject in need twice daily for 30 days.

17. The pharmaceutical composition according to any of the preceding claims, wherein the treatment comprises administering the composition to the subject in need for at least 30 days.

18. A method for improving muscle mass in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

19. A method of treating a subject with cirrhosis, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

20. A method of treating a subject suffering from sarcopenia, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

21. The method according to any one of claims 18 to 220, wherein the pharmaceutical composition has a multi-matrix structure, the multi-matrix structure comprising: a. It incorporates an amphiphilic matrix containing rifamycin SV; b. Formed from a substance with a melting point below 90°C and wherein a) is dispersed a lipophilic matrix; and c. Hydrophilic matrix.

22. The method of claim 20, wherein the amphiphilic matrix comprises a substance selected from the group consisting of: phospholipids, ceramides, sphingomyelin, type I or type II polar lipids, lecithin, alkyl block copolymers, sulfated alkyl salts, polyoxyethylene alkyl derivatives of sorbitan, ethylene glycol alkyl ethers, natural or synthetic gums, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate and / or ethylene and / or propylene block copolymers.

23. The method according to any one of claims 20 to 22, wherein the lipophilic matrix comprises a substance selected from the group consisting of: unsaturated or hydrogenated alcohols or fatty acids, their salts or esters; fatty acid monoglycerides, diglycerides or triglycerides or their polyethoxylated derivatives; waxes; ceramides; cholesterol derivatives or mixtures thereof; stearic acid or its salts.

24. The method according to any one of claims 20 to 23, wherein the hydrophilic matrix comprises a substance selected from the group consisting of: cellulose derivatives and their esters and / or salts, hydroxyalkyl cellulose, alkyl cellulose, carboxylalkyl cellulose and their salts or derivatives, polyvinyl alcohol, carboxyvinyl derivatives, polysaccharide derivatives, dextrin, pectin, starch and its derivatives, anionic or cationic polysaccharides, hyaluronic acid, glucuronic acid, or glucosamine, pectin and / or its derivatives, natural or synthetic gums; alginic acid; polyols, xylitol, maltitol, or mannitol.

25. The method according to any one of claims 18 to 24, wherein the composition further comprises a gastric-tolerant coating.

26. The method according to any one of claims 18 to 25, wherein the composition comprises a tablet core and a coating covering the core.

27. The method according to any one of claims 18 to 26, wherein the composition is suitable for oral administration.

28. The method according to any one of claims 18 to 27, wherein the composition comprises at least about 200 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

29. The method according to any one of claims 18 to 28, wherein the composition comprises about 600 mg of rifamycin SV or a pharmaceutically acceptable salt thereof.

30. The method of claim 220, wherein the treatment comprises administering about 600 mg of rifamycin SC or a pharmaceutically acceptable salt thereof to a subject in need.

31. The method according to any one of claims 18 to 29, wherein the subject suffers from a chronic disease.

32. The method of claim 31, wherein the chronic disease is selected from the group consisting of: cirrhosis, hepatic encephalopathy, cancer cachexia, renal failure, congestive heart failure, and end-stage lung disease.

33. The method according to claim 31 or 32, wherein the chronic disease is cirrhosis and / or hepatic encephalopathy.

34. The method according to any one of claims 18 to 33, wherein the treatment comprises administering the composition to the subject in need twice daily.

35. The method according to any one of claims 18 to 34, wherein the treatment comprises administering the composition to the subject in need twice daily for 30 days.

36. The method according to any one of claims 18 to 35, wherein the treatment comprises administering the composition to the subject in need for at least 30 days.

37. The method according to any one of the preceding claims, wherein the subject has been diagnosed with sarcopenia prior to administration of the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

38. The method according to any one of the preceding claims, wherein the subject has been diagnosed with mild hepatic encephalopathy prior to administration of the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

39. The method according to any one of the preceding claims, wherein the subject has been diagnosed with cirrhosis prior to administration of the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

40. The method according to any one of the preceding claims, wherein the subject has been diagnosed with relevant cognitive impairment prior to administration of the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

41. The method according to any one of the preceding claims, wherein the subject did not have diarrhea prior to administration of the pharmaceutical composition comprising rifamycin SV or a pharmaceutically acceptable salt thereof and one or more carriers and / or excipients.

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